Treatment overview

Traditional treatment options are effective for many patients with PV but do not target the molecular underpinnings of the disease and are associated with several limitations, suggesting that improved treatment options are warranted. The goals of treatment in PV are to reduce the risk of cardiovascular/thrombotic events and control disease-related symptoms.16 Maintaining a hematocrit level of <45% is associated with a reduced risk of cardiovascular/thrombotic events and related death.20 For patients with splenomegaly, treatment should also aim to reduce spleen size.72 Aspirin, phlebotomy, and cytoreduction are the three main elements of traditional PV treatment strategies.16,72

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The European Collaboration on Low-Dose Aspirin in Polycythemia Vera clinical trial demonstrated that treatment with low-dose aspirin was associated with a reduced risk of cardiovascular/thrombotic events.19 Subsequently, a Cochrane meta-analysis reported that low-dose aspirin was associated with a nonsignificant reduction in the risk of fatal thrombotic events.73 However, patients receiving regular aspirin treatment (≥2×325 mg/wk) may be at a dose-dependent increased risk of gastrointestinal bleeding.74 Aspirin is contraindicated in patients with acquired von Willebrand syndrome and/or platelet count of >1,000×109/L, which are associated with an increased risk of bleeding.75,76


Phlebotomy with or without cytoreductive treatment to maintain a hematocrit level of <45% was associated with reduced cardiovascular death and major thrombotic events in patients with PV.20 However, hematocrit maintenance at <45% with phlebotomy and other traditional treatment options can be difficult. The CYTO-PV study required hematocrit control within predefined limits with phlebotomy and/or other traditional treatments (eg, aspirin and cytoreductive therapy); however, >25% of the patients did not maintain hematocrit levels within their target range.77

Phlebotomy procedures may be poorly tolerated by some patients, as evidenced by the observation that 28% of patients in the high-hematocrit arm of the CYTO-PV trial discontinued phlebotomy treatment.20 In a large study of phlebotomy patients undergoing venipuncture (N=3,315), 15% of patients reported that they feared the phlebotomy procedure and 3% reported that they avoided the procedure because of that fear.78 In addition, frequent phlebotomies can cause iron deficiency, which may be associated with restless leg syndrome and impairments in cognitive functioning and mental health in some patients.79-81

Cytoreductive agents

Cytoreductive treatment with hydroxyurea is associated with increased survival and may be associated with reduced thromboembolic risk in patients with PV.17,18 However, one retrospective study indicated that 11% and 13% of patients treated with hydroxyurea become resistant and intolerant, respectively.21 In a multivariate analysis, resistance to hydroxyurea was associated with a 6.8-fold higher risk of transformation to AML or MF and a 5.6-fold higher risk of death.21 Hydroxyurea may also be associated with several hematologic and nonhematologic side effects that could limit treatment, including leg ulcers and other mucocutaneous manifestations, gastrointestinal toxicity, and fever.21

Some data suggest that hydroxyurea may increase the risk of transformation to leukemia, especially in younger patients, although further analyses are required to confirm this hypothesis.82,83 The PV Study Group-08 trial reported that the incidence of AML at a median follow-up of 8.6 years was 5.9% in 51 hydroxyurea-treated patients compared with 1.5% in a historical control group of 134 patients from the phlebotomy-only arm of an earlier study; however, the difference between treatment groups was not statistically significant.18 In an analysis of 1,638 patients with PV enrolled in a prospective observational cohort study with a median follow-up of 2.8 years, the incidence of AML/myelodysplastic syndrome (MDS) in patients treated with hydroxyurea was not significantly different from that of patients receiving no treatment, phlebotomy, or interferon.84 The French Polycythemia Study Group was a large, randomized trial with a median follow-up of 16.3 years that compared hydroxyurea with pipobroman as first-line treatment of PV in 285 patients <65 years of age.17 The cumulative incidences of progression to AML/MDS at 10 years, 15 years, and 20 years were 6.6%, 16.5%, and 24.2%, respectively, in the hydroxyurea group and 13.1%, 34.1%, and 52.1%, respectively, in the pipobroman group. The authors acknowledged that the incidence of transformation to AML/MDS in hydroxyurea-treated patients was higher than previously reported. However, they emphasized that the natural evolution of PV should be considered when interpreting the study results. The leukemogenic risk of hydroxyurea appears to be increased when treatment is preceded or followed by alkylating agents (eg, busulfan).83,85 Because hydroxyurea may modestly increase the risk of AML development, it has been suggested that this drug should be used with caution in younger patients (<40 years of age) with MPNs.82

Interferon-α (IFN-α) and pegylated (PEG)-IFN-α variants are not currently indicated by the US Food and Drug Administration (FDA) or the European Medicines Agency for the treatment of patients with PV. However, IFN-α was recommended by the European LeukemiaNet in 2011 as second-line cytoreductive therapy for patients with PV who become resistant to or intolerant of hydroxyurea.86 Treatment with IFN-α and PEG-IFN-α variants has been associated with hematocrit control without phlebotomy, normalization of blood cell counts, and reductions in enlarged spleen size.87-89 In a review article that summarized clinical trial experience with different IFN-α variants in patients with PV published between 1991 and 2008, 60% (182/303) of patients achieved freedom from phlebotomies.90 An objective response was observed in ~80% of patients, although response criteria were heterogenous among these studies.90 In addition, some data suggest that IFN-α treatment may be associated with improvements in some PV-related signs and symptoms, including pruritus91,92 and splenomegaly.87,88,93,94 However, the route of administration (injection) and safety concerns about recombinant IFN-α formulations suggest that IFN-α may not be an ideal treatment option for some patients. A multicenter observational study reported that nonadherence to IFN-α primarily resulted from patients forgetting to administer the injection (50.2%) and other injection-related reasons (32.0%).95 Side effects of IFN-α, including influenza-like symptoms,96 autoimmune disorders, depression, cardiovascular disease, and ocular disease,16 may lead some patients to discontinue the treatment.97 These safety concerns are primarily associated with recombinant IFN-α variants, and it is important to note that PEG-IFN-α variants are associated with fewer toxicity-related treatment discontinuations.97 PEG-IFN-α2a has also demonstrated decreases in JAK2V617F allele burden over time and is associated with preferable hematologic responses in patients with PV.97,98 In two Phase II clinical trials evaluating PEG-IFN-α in patients with PV, complete hematologic response was observed in 70% and 94.6% of patients (median follow-up time, 21 months and 31.4 months, respectively), and complete molecular response (undetectable JAK2V617F) was observed in 14% and 24.1% of evaluable patients, respectively.89,97 Discontinuations because of PEG-IFN-α-related adverse events were 10% and 24.3% in these studies.89,97 Further analyses from ongoing Phase III trials (eg, identifiers: NCT01259856, NCT02218047, NCT02523638, NCT01949805, NCT01387763) will be important for determining the role of PEG-IFN-α in treating patients with PV.

Challenges of PV-related symptom alleviation

Traditional treatment options may not alleviate the PV-related symptom burden.23,24 In a survey-based study, patients with MPNs treated with hydroxyurea, IFN-α, busulfan, or 32P reported similar MPN-SAF symptom severity scores as patients who did not receive myelosuppressive agents.23 Furthermore, a prospective analysis of patients with PV reported that treatment with hydroxyurea, aspirin, IFN-α, or phlebotomy was not associated with significant improvements in the MPN-SAF total symptom score (TSS).24 Collectively, available data suggest that a targeted treatment approach aimed at the molecular pathway associated with the pathogenesis of PV could be more effective than traditional treatment options for ameliorating PV-related symptoms.